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J. Biol. Chem., Vol. 281, Issue 24, 16799-16813, June 16, 2006

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Differential Interactions between Transforming Growth Factor-3/TR1, TAB1, and CD2AP Disrupt Blood-Testis Barrier and Sertoli-Germ Cell Adhesion^*

Weiliang Xia, Dolores D. Mruk, Will M. Lee, and C. Yan Cheng¹

From the Population Council, Center for Biomedical Research, New York, New York 10021 and Department of Zoology, University of Hong Kong, Hong Kong, China

The biochemical basis that regulates the timely and selective opening of the blood-testis barrier (BTB) to migrating preleptotene/leptotene spermatocytes at stage VIII of the epithelial cycle in adult rat testes is virtually unknown. Recent studies have shown that cytokines (e.g. transforming growth factor (TGF)-3) may play a crucial role in this event. However, much of this information relies on the use of toxicants (e.g. CdCl₂), making it difficult to relay these findings to normal testicular physiology. Here we report that overexpression of TGF-3 in primary Sertoli cells cultured in vitro indeed perturbed the tight junction (TJ) barrier with a concomitant decline in the production of BTB constituent proteins as follows: occludin, N-cadherin, and ZO-1. Additionally, local administration of TGF-3 to testes in vivo was shown to reversibly perturb the BTB integrity and Sertoli-germ cell adhesion via the p38 MAPK and ERK signaling pathways. Most importantly, the simultaneous activation of p38 and ERK signaling pathways is dependent on the association of the TGF-3-TR1 complex with adaptors TAB1 and CD2AP because if TR1 was associated preferentially with CD2AP, only Sertoli-germ cell adhesion was perturbed without compromising the BTB. Collectively, these data illustrate that local production of TGF-3, and perhaps other TGF-s and cytokines, by Sertoli and germ cells into the microenvironment at the BTB during spermatogenesis transiently perturbs the BTB and Sertoli-germ cell adhesion to facilitate germ cell migration when the activated TRI interacts with adaptors TAB1 and CD2AP. However, TGF-3 selectively disrupts Sertoli-germ cell adhesion in the seminiferous epithelium to facilitate germ cell migration without compromising BTB when TRI interacts only with adaptor CD2AP.

Received for publication, February 21, 2006 , and in revised form, April 13, 2006.

^* This work was supported in part by NICHD Grants U01 HD045908 and U54 HD029990, Project 3 (to C. Y. C.), from the National Institutes of Health, CONRAD Program Grant CICCR, C1G 01-72 (to C. Y. C.), and Hong Kong Research Grant Council Grant HKU 7413/04M (to W. M. L.). The costs of publication of this article were defrayed in part by the payment of page charges. This article must therefore be hereby marked "advertisement" in accordance with 18 U.S.C. Section 1734 solely to indicate this fact.

¹ To whom correspondence should be addressed: Population Council, 1230 York Ave., New York, NY 10021. Fax: 212-327-8733; E-mail: Y-Cheng{at}popcbr.rockefeller.edu.

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